Abstract
Despite being routinely used for pain management, opioid use is limited due to adverse effects such as development of tolerance and paradoxical pain, including thermal hyperalgesia and mechanical allodynia. Evidence indicates that continued morphine administration causes increased expression of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α). The objectives of the present study were to determine the effects of B1 (N-[(1H-benzimidazol-2-yl)methyl]-4-methoxyaniline) and B8 (N-{4-[(1H-benzimidazol-2-yl)methoxy]phenyl}acetamide), benzimidazole derivatives, on thermal nociception and mechanical allodynia during repeated morphine (intraperitoneal; 5 mg/kg twice daily for 6 days)-induced paradoxical pain and TNF-α expression in the spinal cord in mice. Our data indicate that administration of benzimidazole derivatives attenuated morphine-induced thermal hyperalgesia and mechanical allodynia. Benzimidazole derivatives also reduced TNF-α expression in mice. Taken together, these results suggest that benzimidazole derivatives might be useful for the treatment of neuroinflammatory consequences of continued morphine administration and could be potential drug candidates for the management of opioid-induced paradoxical pain.
Highlights
Pain is a significant social, clinical, and economic health problem (Phillips, 2006)
Paw withdrawal latency in mice treated with B1 (9 mg/kg) was 10.66 ± 1.4 s (∗∗∗p < 0.001) on day 7, and 9.5 ± 96 s (∗∗p < 0.01) at 96 h after withdrawal, relative to the vehicle-morphine group (Figure 3A)
The mean paw withdrawal latency of the mice treated in the morphine-ketamine positive control group was 12.83 ± 1.01 s (∗p < 0.05) on day 5, 13 ± 1.31 s (∗∗∗p < 0.001) on day 7, and 11.16 ± 1.22 s (∗∗∗p < 0.001) at 96 h after withdrawal, relative to the vehicle-morphine group (Figures 3A,B)
Summary
Pain is a significant social, clinical, and economic health problem (Phillips, 2006). It usually results from activation of nociceptive afferents by actual or potential tissue-damaging stimuli (Treede et al, 2008). Opioids such as morphine remain the drug of choice in alleviating moderate to severe pain (Johnston et al, 2004). Long-term opioid treatment is associated with reduced clinical efficacy and paradoxical pain development characterized by hyperalgesia and allodynia in humans and in experimental animals (Tompkins and Campbell, 2011). It has been reported that the prolonged use of morphine may result neuro-inflammation in the central nervous system and hyperalgesia that leads to the suppression of morphine analgesia (Wang et al, 2012)
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